CAD is a multi-subunit enzyme formed by hexameric association of three functional domains: glutamine-dependent carbamoyl phosphate synthetase, aspartate transcarbamoylase (ATCase), and dihydroorotase. CAD catalyzes the first three steps in the de novo synthesis of pyrimidines, and its activity is essential to supply the high demand of nucleotides during cell growth and proliferation, making CAD a potential drug target for the development of cancer therapeutics. N-phosphonacetyl-L-aspartate (PALA) is a potent inhibitor of the ATCase domain. It is a transition-state analog of ATCase based on the structures of its two substrates, aspartate and carbamoyl phosphate, as well as the structure of the bacterial enzyme. The recent report of the first crystal structure of human ATCase, free and bound to PALA, provides insight into the inhibition of this subunit of CAD. In the human ATCase, only two of the three active sites show high affinity for PALA, offering new hints to understanding tumor resistance to PALA that plagued its clinical trials. Here we report the design, synthesis, and evaluation of a series of PALA derivatives as potential human ATCase inhibitors.

Design, synthesis, and evaluation of N-phosphonacetyl-L-aspartate derivatives as putative human ATCase inhibitors

254th National Meeting (2017)

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